Aripiprazole, i.e., 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone, is an antipsychotic drug useful in the treatment of schizophrenia and the like (Patent Literature 1 and Patent Literature 2).
Aripiprazole takes various forms, and is known to be present in monohydrate form (aripiprazole hydrate A) and other numerous anhydrous forms, i.e., anhydride crystals B, anhydride crystals C, anhydride crystals D, anhydride crystals E, anhydride crystals F, and anhydride crystals G.
Aripiprazole has been provided as a pharmaceutical product in the form of fine particles of anhydride crystals B.
When aripiprazole anhydride crystals B are used in the form of particles having a small particle size (less than 50 μm), anhydride crystals B having a large particle size must be milled. However, direct milling of anhydride crystals B has a problem such that milled drugs adhere to each other in the milling device. Therefore, it was difficult to produce aripiprazole anhydride crystals B having a small particle size on the industrial level (see Patent Literature 3, paragraph [0249]).
In order to solve this problem, it was found that aripiprazole anhydride crystals B having a small particle size can be prepared in the following manner: crude aripiprazole is crystallized in hydrous ethanol (water content is 20 vol %) to first prepare aripiprazole hydrate crystals A that can be easily milled; the thus-prepared hydrate crystals A are dry-milled (using a small atomizer) to obtain a fine particle size (20 to 25 μm); and the resulting product is heated at 90 to 125° C. (see Patent Literature 3, paragraphs [0250] to [0251]; Reference Examples 1 and 2; and Examples 1 to 4).
However, the above method for producing aripiprazole anhydride crystals B requires a multi-stage process, i.e., first obtaining aripiprazole hydrate crystals A; dry-milling the same; and further heating the same. Therefore, there has been a desire for an even shorter process in terms of cost and labor.
Patent Literature 4 discloses the crystalline form of alcohol solvates of aripiprazole (methanolate and ethanolate), and states that solvent-free aripiprazole crystals B can be prepared from alcohol solvates. However, Patent Literature 4 nowhere teaches the preparation of aripiprazole anhydride crystals B in the form of fine particles (average particle size of less than 50 μm), which is a desirable form for pharmaceutical products.
Rather, Patent Literature 4 (page 6, lines 1 to 7) states that hemiethanolates of aripiprazole are unstable for milling, and that the product resulting from milling does not have a form of any known solvent-free aripiprazole: it may be a mixture of Forms B and E, or a new form. In other words, Patent Literature 4 suggests that milling of a hemiethanolate of aripiprazole into fine particles causes contamination; and that, as a result, fine particles of high-purity, solvent-free aripiprazole crystals B cannot be obtained.
Under such a situation, there has been a strong demand for a method for efficiently preparing high-purity aripiprazole anhydride crystals B in the form of fine particles in a short process on an industrial scale.